Alternative macrophage activation limits immunopathology

描述（由申请人提供）：巨噬细胞是异质髓系吞噬细胞，通过尚未解决的机制驱动宿主防御和伤口修复。本项目研究了寄生蠕虫感染后，在宿主免疫和组织修复的背景下，肺巨噬细胞生物学。全世界有超过10亿人感染了寄生虫，受感染的人可能遭受不同程度的肺损伤，这取决于蠕虫的种类。从蠕虫感染个体的胸部x线图像的历史数据显示，抗蠕虫治疗后，组织损伤自发消退。我们的数据表明，肺巨噬细胞对蠕虫诱导的短暂性肺损伤至关重要。这项更新应用将建立肺巨噬细胞抑制病原体特异性炎症、促进再上皮化和恢复肺气体交换功能的机制。我们将在基因上消耗CD68+组织巨噬细胞，监测血氧含量（SpO2），并跟踪促炎2组先天淋巴样细胞（ILC2）和免疫抑制调节性T细胞群，以实现我们的项目目标。我们有证据表明，肺巨噬细胞耗竭导致ILC2扩张增加，并降低损伤肺组织内白细胞介素10水平。此外，我们提供的证据表明，巨噬细胞通过产生Wnt蛋白来驱动再上皮化，Wnt蛋白是上皮细胞再生的既定介质。因此，我们的项目研究钩虫感染期间宿主保护性免疫的机制，作为理解可逆性肺损伤的替代方法。对于数百万患有急性和慢性肺部疾病的人来说，更清楚地了解感染后的肺修复是极其重要的。预计到2020年，急性和慢性肺部疾病将成为美国第三大死亡原因。显然，我们非常需要了解炎症和修复是如何在肺部受到调节的。因此，我们将验证肺巨噬细胞产生限制ILC2扩增和促进调节性T细胞扩增的免疫抑制因子的假设，以及肺巨噬细胞通过依赖wnt4a的机制直接促进上皮再生的假设。这一假设将在以下具体目的中得到验证：目的1将确定肺功能的修复和肺稳态的恢复是否需要肺巨噬细胞或ILC2。Aim 2将确定肺巨噬细胞是否通过IL-10和/或tgf依赖机制抑制ILC2或诱导调节性T细胞扩增，Aim 3将确定巨噬细胞驱动上皮再生的分子机制。这项工作的完成将提供更深入的了解感染诱导的炎症和肺组织再生是如何通过髓系和淋巴系精心安排的。

DESCRIPTION (provided by applicant): Macrophages are heterogeneous myeloid phagocytes that drive host defense and wound repair through unresolved mechanisms. This project investigates lung macrophage biology in the context of host immunity and tissue repair following parasitic helminth infection. More than one billion people worldwide are infected with parasitic helminthes and depending upon the worm species, infected individuals can suffer various degrees of lung injury. Historical data from chest x-ray images of worm-infected individuals revealed spontaneous resolution of tissue damage occurred following anti-helminthic therapy. Our data shows that lung macrophages are essential for the transient nature of helminth induced lung injury. This renewal application will establish the mechanism(s) used by lung macrophages to suppress pathogen-specific inflammation, facilitate re- epithelialization and restore lung gas exchange function. We will genetically deplete CD68+ tissue macrophages, monitor blood oxygen content (SpO2), and track both pro-inflammatory group 2 innate lymphoid cells (ILC2) and immunosuppressive regulatory T cell populations to achieve our project goals. We have evidence that lung macrophage depletion causes increased expansion of ILC2 and reduces interleukin 10 levels within injured lung tissue. Moreover, we provide evidence that macrophages drive re-epithelialization through producing Wnt proteins, which are established mediators of epithelial cell regeneration. Therefore, our project investigates mechanisms of host protective immunity during hookworm infection as a surrogate for understanding reversible lung injury. A clearer understanding of lung repair following infection is extremely important for millions of individuals suffering from acute and chronic forms of lung disease. Combined, acute and chronic lung diseases are predicted to be the 3rd leading cause of death within the United States by 2020. Clearly, there is a great need for understanding how inflammation and repair are regulated within the pulmonary tract. Therefore, we will test the hypothesis that lung macrophages produce immunosuppressive cytokines that limit ILC2 expansion and promote regulatory T cell expansion and also that lung macrophages directly promote epithelial regeneration via a Wnt4a-dependent mechanism. This hypothesis will be tested in the following specific aims: Aim 1 will determine whether repair of pulmonary function and restoration of lung homeostasis requires lung macrophages or ILC2. Aim 2 will determine whether lung macrophages suppress ILC2 or induce regulatory T cell expansion via IL-10 and/or TGF-dependent mechanisms and Aim 3 will identify the molecular mechanism(s) responsible for macrophage-driven epithelial regeneration. Completion of this work will provide a deeper understanding of how infection-induced inflammation and pulmonary tissue regeneration are orchestrated via myeloid and lymphoid lineages.